The invention relates to novel retinoid compounds and methods of synthesis thereof. The invention also relates to methods of using these novel retinoid compounds and pharmaceutical compositions thereof.
The retinoids are structural analogues of vitamin A and include both natural and synthetic compounds. Retinoid compounds such as all trans retinoic acid (xe2x80x9cATRAxe2x80x9d), 9-cis-retinoic acid, trans 3-4 didehydroretinoic acid, 4-oxo retinoic acid, 13-cis-retinoic acid and retinol are pleiotrophic regulatory compounds that influence a large number of inflammatory, immune and structural cells.
For example, retinoids modulate epithelial cell proliferation, morphogenesis in lung and differentiation through a series of hormone nuclear receptors that belong to the steroid/thyroid receptor superfamily. The retinoid receptors are classified into the retinoic acid receptors (RAR) and the retinoid X receptors (RXR) each of which consists of three distinct subtypes (xcex1, xcex2 and xcex3).
ATRA is the natural ligand for the retinoic acid receptors and binds with similar affinity to the xcex1, xcex2 and xcex3 subtypes. A quantitative structure-activity relationship has been established for a number of synthetic RAR xcex1, xcex2 and xcex3 retinoid agonists, which has elucidated the principal electronic and structural characteristics that provide selective affinity for each RAR subtype (Douget et al., Quant. Struct. Act. Relat., 18, 107, 1999).
ATRA does not bind to RXR, for which 9-cis-retinoic acid is the natural ligand. A number of synthetic RXR xcex1, xcex2 and xcex3 retinoid agonists have also been described in the art (See, e.g., Billoni et al., U.S. Pat. No. 5,962,508; Klaus et al., U.S. Pat. No. 5,986,131.
In tissues other than pulmonary tissues, retinoids typically have anti-inflammatory effects, can alter the progression of epithelial cell differentiation and may inhibit stromal cell matrix production. These biological effects of retinoids have led to the development of many topical agents for dermatological disorders such as psoriasis, acne, and hypertrophic cutaneous scars. Retinoids have also been used in the treatment of light and age damaged skin, the healing of wounds caused, for example, by surgery and burns (Mustoe et al., Science 237, 1333 1987; Sprugel et al., J. Pathol., 129, 601, 1987; Boyd, Am. J. Med., 86, 568, 1989) and as anti-inflammatory agents for treatment of arthritis. Other medicinal applications of retinoids include the control of acute promyelocytic leukemia, adeno and squamous cell carcinoma and hepatic fibrosis. Retinoids have also been used extensively in treatment of premalignant epithelial lesions and malignant tumors (carcinomas) of epithelial origin (Bollag et al., U.S. Pat. No. 5,248,071; Sporn et al., Fed. Proc. 1976, 1332; Hong et al., xe2x80x9cRetinoids and Human Cancerxe2x80x9d in The Retinoids: Biology, Chemistry and Medicine, M. B. Sporn, A. B. Roberts and D. S. Goodman (eds.) Raven Press, New York, 1994, 597-630). However, many retinoids previously studied often lack selectivity and consequently exert harmful pleiotrophic effects and may cause patient death when used in therapeutically effective amounts. Thus, the therapeutic use of retinoids in diseases other then cancer has been limited by toxic side effects. A general review of retinoids can be found in Goodman and Gilman""s xe2x80x9cThe Pharmacological Basis of Therapeuticsxe2x80x9d, 9th edition (1996, McGraw-Hill) Chapters 63-64.
Chronic Obstructive Pulmonary Disease (xe2x80x9cCOPDxe2x80x9d) refers to a large group of lung diseases which prevent normal respiration. Approximately 11% of the population of the United States has COPD and available data suggests that the incidence of COPD is increasing. Currently, COPD is the fourth leading cause of mortality in the United States.
COPD is a disease in which the lungs are obstructed due to the presence of at least one disease selected from asthma, emphysema and chronic bronchitis. The term COPD was introduced because these conditions often co-exist and in individual cases it may be difficult to ascertain which disease is responsible for causing the lung obstruction (1987 Merck Manual). Clinically, COPD is diagnosed by reduced expiratory flow from the lungs that is constant over several months and in the case of chronic bronchitis persists for two or more consecutive years. The most severe manifestations of COPD typically include symptoms characteristic of emphysema.
Emphysema is a disease where the gas-exchange structures (e.g., alveoli) of the lung are destroyed, which causes inadequate oxygenation that may lead to disability and death. Anatomically, emphysema is defined by permanent airspace enlargement distal to terminal bronchioles (e.g., breathing tubes) which is characterized by reduced lung elasticity, decreased alveolar surface area and gas exchange and alveolar destruction that results in decreased respiration. Thus, the characteristic physiological abnormalities of emphysema are reduced gas exchange and expiratory gas flow.
Cigarette smoking is the most common cause of emphysema although other environmental toxins may also contribute to alveoli destruction. The injurious compounds present in these harmful agents can activate destructive processes that include, for example, the release of excessive amounts of proteases that overwhelm normal protective mechanisms, such as protease inhibitors present in the lung. The imbalance between proteases and protease inhibitors present in the lung may lead to elastin matrix destruction, elastic recoil loss, tissue damage, and continuous lung function decline. The rate of lung damage may be decreased by reducing the amounts of toxins in the lung (i.e., by quitting smoking). However, the damaged alveolar structures are not repaired and lung function is not regained. At least four different types of emphysema have been described according to their locations in the secondary lobule: panlobar emphysema, centrilobular emphysema, distal lobular emphysema and paracicatrical emphysema.
The major symptom of emphysema is chronic shortness of breath. Other important symptoms of emphysema include but are not limited to chronic cough, coloration of the skin caused by lack of oxygen, shortness of breath with minimal physical activity and wheezing. Additional symptoms that may be associated with emphysema include but are not limited to vision abnormalities, dizziness, temporary cessation of respiration, anxiety, swelling, fatigue, insomnia and memory loss. Emphysema is typically diagnosed by a physical examination that shows decreased and abnormal breathing sounds, wheezing and prolonged exhalation. Pulmonary function tests, reduced oxygen levels in the blood and a chest X-ray may be used to confirm a diagnosis of emphysema.
No effective methods for reversing the clinical indications of emphysema currently exist in the art. In some instances, medications such as bronchodilators, xcex2-agonists, theophylline, anticholinergics, diuretics and corticosteroids delivered to the lung by an inhaler or nebulizer may improve respiration impaired by emphysema. Oxygen treatment is frequently used in situations where lung function has been so severely impaired that sufficient oxygen cannot be absorbed from the air. Lung reduction surgery may be used to treat patients with severe emphysema. Here, damaged portions of the lung are removed, which allows the normal portions of the lung to expand more fully and benefit from increased aeration. Finally, lung transplantation is another surgical alternative available to individuals with emphysema, which may increase quality of life but does not significantly improve life expectancy.
Alveoli are formed during development by division of sacchules that constitute the gas-exchange elements of the immature lung. The precise mechanisms governing formation of septa and their spacing remain currently unknown in primates. Retinoids such as ATRA, which is a multifunctional modulator of cellular behavior that may alter both extracellular matrix metabolism and normal epithelial differentiation, have a critical regulatory role in mammals such as the rat. For example, ATRA modulates critical aspects of lung differentiation through binding to specific retinoic acid receptors that are selectively temporally and spatially expressed. Coordinated activation of different retinoic acid receptors subtypes has been associated with lung branching, alveolization/septation and gene activation of tropoelastin in neonatal rats.
During alveolar septation, retinoic acid storage granules increase in the fibroblastic mesenchyme surrounding alveolar walls (Liu et al., Am. J. Physiol. 1993, 265, L430; McGowan et al., Am. J. Physiol., 1995, 269, L463) and retinoic acid receptor expression in the lung peaks (Ong et al., Proc. Natl. Acad. of Sci., 1976, 73, 3976; Grummer et al., Pediatr. Pulm. 1994, 17, 234). The deposition of new elastin matrix and septation parallels depletion of these retinoic acid storage granules. Postnatal administration of retinoic acid has been shown to increase the number of alveoli in rats, which supports the concept that ATRA and other retinoids may induces alveoli formation (Massaro et al., Am. J. Physiol., 270, L305, 1996). Treatment of newborn rat pups with dexamethasone, a glucocorticosteroid, prevents septation and decreases expression of some sub-types of retinoic acid receptor. Supplemental amounts of ATRA have been shown to prevent dexamethasone inhibition of alveoli formation. Further, ATRA prevents dexamethasone from diminishing retinoic acid receptor expression and subsequent alveolar septation in developing rat lung.
ATRA has been reported to induce formation of new alveoli and returns elastic recoil in the lung to approximately normal values in animal models of emphysema (Massaro et al., Nature Med., 1997, 3, 675; xe2x80x9cStrategies to Augment Alveolization,xe2x80x9d National Heart, Lung, and Blood Institute, RFA: HL-98-011, 1998; Massaro et al., U.S. Pat. No. 5,998,486). However, the mechanism of action of ATRA in these studies remains undefined, although Massaro reports that ATRA generates new alveoli. More importantly, the use of ATRA presents several toxicity or adverse effects concerns.
Thus, novel retinoid agonists useful for treating dermatological disorders, emphysema and cancer without the toxicity problems of ATRA or other retinoids are highly desirable.
The current invention provides novel retinoid agonists, methods of treating or preventing emphysema, cancer and dermatological disorders, pharmaceutical compositions suitable for the treatment or prevention of emphysema, cancer and dermatological disorders and methods for delivering formulations of novel retinoids into the lung of a mammal suffering from emphysema, cancer and dermatological disorders.
In one embodiment, the invention provides compounds having the structural formula (I): 
or a pharmaceutically acceptable salt, solvate hydrate or prodrug thereof wherein:
n is an integer from 0 to 2;
c is 0 or 1;
d is 0 or 1;
A is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90CH2)xe2x80x94, xe2x80x94C(xe2x95x90NR4)xe2x80x94 or xe2x80x94CR5R6xe2x80x94;
R4 is hydrogen, alkyl, hydroxy, alkoxy or amino; and
R5 and R6 are independently hydrogen, alkyl or together, along with the carbon to which they are both attached, are cycloalkyl;
B is xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHC(O)NHxe2x80x94, xe2x80x94CR7xe2x95x90CR8xe2x80x94, xe2x80x94R7Cxe2x95x90CR8xe2x80x94C(O)xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94C(O)xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94COCH2xe2x80x94, or xe2x80x94CH2COxe2x80x94;
R7 and R8 are independently hydrogen or alkyl;
with the provisos that:
when A is xe2x80x94C(xe2x95x90O)xe2x80x94, or xe2x80x94C(xe2x95x90NR4)xe2x80x94, then B is not xe2x80x94OC(O)xe2x80x94; and
when A is xe2x80x94C(xe2x95x90CH2)xe2x80x94, then B is not xe2x80x94OC(O)xe2x80x94;
X is aryl or heteroaryl;
R1 is xe2x80x94C(xe2x95x90O)xe2x80x94R9;
R9 is alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, aryloxy, cycloalkyloxy, cycloalkyl-alklyloxy, arylalkyloxy, amino, alkylamino, dialkylamino, heteroalkyloxy, heteroalkylamino, heteroalkylthio, heterocyclyl or heterocyclylalkyl; and
R2 is:
(a) xe2x80x94(CR10R11)mxe2x80x94Ypxe2x80x94R12;
m is an integer from 1 to 10;
p is 0 or 1;
R10 and R11 are independently hydrogen, alkyl, hydroxy or hydroxyalkyl;
Y is xe2x80x94Oxe2x80x94, xe2x80x94S(O)qxe2x80x94 or xe2x80x94NR13xe2x80x94; and
q is an integer from 0 to 2; and
R13 is hydrogen or alkyl;
R12 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxycarbonyl, carbamoyl, substituted cycloalkyl, heteroalkyl, heteroalkylsubstituted cycloalkyl, hetero substituted cycloalkyl, hetero substituted cycloalkyl-alkyl, heterocyclyl or heterocyclylalkyl;
with the proviso that when p=0, then R12 is not hydrogen or alkyl;
(b) heteroaryl;
(c) xe2x80x94Zxe2x80x94L; where:
Z is xe2x80x94CR14xe2x95x90CR15xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR16xe2x80x94, or xe2x80x94C(xe2x95x90O) or xe2x80x94S(O)qxe2x80x94;
R14, R15 and R16 are independently hydrogen or alkyl; and
L is heteroaryl, heteroarylalkyl or heteroalkyl
with the proviso that when Acxe2x80x94Bd is xe2x80x94C(xe2x95x90O)xe2x80x94CR7xe2x95x90CR8xe2x80x94, then L is not heteroalkyl; or
(d) xe2x80x94CR14xe2x95x90CR15xe2x80x94L1 where L1 is S(O)2R17 or SO2NR18R19 where R17 is alkyl and
R18 and R19 are independently hydrogen or alkyl;
each R3 is independently hydrogen, alkyl, hydroxy or oxo; and
t is 1 or 2.
In a preferred embodiment, the invention provides compounds having the structural formula (II): 
or a pharmaceutically acceptable salt, solvate or hydrate thereof wherein A, B, c, d, X, R1, R3, n, R10, R11, m, Y, p and R12 are as previously defined.
In another preferred embodiment, the invention provides compounds having the structural formula (III): 
or a pharmaceutically acceptable salt, solvate or hydrate thereof wherein A, B, c, d, X, R1, R3 and n are as previously defined.
In still another embodiment, the invention provides compounds having the structural formula (IV): 
or a pharmaceutically acceptable salt, solvate or hydrate thereof wherein A, B, c, d, X, R1, R3, n, Z and L are as previously defined.
In still another embodiment of generic formula (I), c is 0, d is 1, B is xe2x80x94CR7xe2x95x90CR8xe2x80x94 and n, R1, R2 R3, R7, R8 and X are as previously defined. Preferably, R7 and R8 are hydrogen.
In a more specific embodiment, X is aryl. In a preferred embodiment, the invention provides compounds having the structural formula (V): 
or a pharmaceutically acceptable salt, solvate or hydrate thereof wherein n, R1, R2 and R3 are as previously defined. In another preferred embodiment, the invention provides compounds having the structural formula (VI): 
or a pharmaceutically acceptable salt, solvate or hydrate thereof wherein n, R1, R2 and R3 are as previously defined.
In another specific embodiment, X is heteroaryl. In this embodiment, the invention provides compounds having the structural formula (VII): 
or a pharmaceutically acceptable salt, solvate or hydrate, thereof wherein n, R1, R2 and R3 are as previously defined. In all of the embodiments hitherto described, also preferred are those where R1 is xe2x80x94CO2H or xe2x80x94CO2-alkyl, particularly xe2x80x94CO2H. Furthermore, also preferred are those embodiments where R3 is hydrogen and n and t are 1.
Another embodiment of the invention is represented by compounds of structural formula VIII, 
wherein:
R20 is alkyl;
R21 is: (a) heteroalkyloxy, heteroalkylamino, or heteroalkylthio; or
(b) Qxe2x80x94R22 where Q is xe2x80x94Oxe2x80x94, xe2x80x94NR23xe2x80x94 or xe2x80x94Sxe2x80x94 (where R23 is hydrogen or alkyl) and
R22 is carboxyalkyl;
and n is an integer from 0 to 2.
The present invention also encompasses the use of the compounds of the invention to treat or prevent certain chronic obstructive airway disorders, particularly chronic obstructive pulmonary disease including chronic bronchitis, emphysema and asthma in mammals, especially humans that smoke or smoked cigarettes. In a preferred embodiment, the invention encompasses the treatment or prevention of panlobar emphysema, centrilobular emphysema or distal lobular emphysema in mammals using therapeutically effective doses of the compounds of the invention.
In one embodiment, the present invention encompasses the use of the compounds of the invention for treating or preventing emphysema. Further, the instant invention encompasses the use of pharmaceutical compositions of the compounds of the invention to treat or prevent emphysema. Moreover, the invention encompasses the use of electrohydrodynamic aerosol devices, aerosol devices and nebulizers to deliver formulations of compounds of the invention into the lung of a mammal suffering from or at risk of emphysema.
The invention encompasses the systemic use as well as the local use of the compounds of the invention or both in combination. Either or both can be achieved by the oral, mucosal or parenteral modes of administration. As mentioned above, means of delivering compounds of the invention directly into the lung by nebulizer, inhaler or other known delivery devices are encompassed by the invention.
A method for treating emphysema by combining compounds of the invention with one or more additional therapies such as smoking cessation (where appropriate) bronchodilators, antibiotics, oxygen therapy and the like is also encompassed by the invention.
In another aspect, the current invention encompasses methods for preventing emphysema in a human at risk of emphysema through administration of an amount of a compound of the invention, or pro-drug thereof, that is sufficient to prevent emphysema. In a another aspect, the current invention encompasses pharmaceutical compositions for preventing emphysema in a human at risk of emphysema through administration of a amount of a compound of the invention or pro-drug thereof, in a pharmaceutically acceptable carrier, that is sufficient to prevent emphysema.
In another aspect, the present invention encompasses the use of compounds of the invention for treating or preventing cancer. Further, the instant invention encompasses the use of pharmaceutical compositions of compounds of the invention to treat or prevent cancer. Moreover, the current invention encompasses the use of electrohydrodynamic aerosol devices, aerosol devices and nebulizers to deliver formulations of compounds of the invention into the lung of a mammal suffering from or at risk of cancer. Cancers include solid tumours such as breast, lung, prostate and liver cancer, promyelocytary leukaemias, precancerous changes of the mucosa in the mouth, tongue, larynx, oesophagus, bladder, cervix and colon.
A method for treating cancer by combining compounds of the invention with one or more additional therapies is also encompassed by the invention. Additional therapies include DNA intercalating agents such as cis-platin and immunotherapeutic agents such as gamma interferons and other cytokines.
In another aspect, the current invention encompasses methods for preventing cancer in a human at risk of cancer through administration of an amount of a compound of the invention, or a pro-drug thereof, that is sufficient to prevent cancer. In another aspect, the current invention encompasses pharmaceutical compositions for preventing cancer in a human at risk of cancer through administration of a amount of a compound of the invention or pro-drug thereof, in a pharmaceutically acceptable carrier, that is sufficient to prevent cancer.
In another aspect, the present invention encompasses the use of compounds of the invention for treating or preventing dermatological disorders. Further, the instant invention encompasses the use of pharmaceutical compositions of compounds of the invention to treat or prevent dermatological disorders. Dermatological disorders include acne, psoriasis, photodamaged skin and other dermatoses accompanied by cornification. Also included are wound healing, e.g., cuts, burns, operation wounds and other wounds associated with cutaneous trauma.
A method for treating dermatological disorders by combining compounds of the invention with one or more additional therapies and the like is also encompassed by the invention.
In another aspect, the current invention encompasses methods for preventing dermatological disorders in a human at risk from dermatological disorders through administration of an amount of a compound of the invention, or a pro-drug thereof, that is sufficient to prevent dermatological disorders. In a final aspect, the current invention encompasses pharmaceutical compositions for preventing emphysema in a human at risk from dermatological disorders through administration of a amount of a compound of the invention or pro-drug thereof, in a pharmaceutically acceptable carrier, that is sufficient to prevent dermatological disorders.
As used herein the term xe2x80x9ccompounds of the inventionxe2x80x9d means the compounds of generic formula (I-VII) including but not limited to specific compounds within those formulas disclosed herein. The compounds of the invention are identified herein by their chemical structure and/or chemical name. Where a compound is referred to by both a chemical structure and a chemical name and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound""s identity. The compounds of the invention may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass all of the corresponding compound""s enantiomers and stereoisomers, that is, the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers using either separation techniques or chiral synthesis techniques known in the art.
xe2x80x9cAcylxe2x80x9d means a radical xe2x80x94C(O)R, where R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or arylalkyl wherein alkyl, cycloalkyl, cycloalkyl-alkyl, aryl and arylalkyl are as defined herein. Representative examples include, but are not limited to formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.
xe2x80x9cAcylaminoxe2x80x9d means a radical xe2x80x94NRxe2x80x2C(O)R, where Rxe2x80x2 is hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or arylalkyl wherein alkyl, cycloalkyl, cycloalkyl-alkyl, aryl and arylalkyl are as defined herein. Representative examples include, but are not limited to formylamino, acetylamino, cylcohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino, and the like.
xe2x80x9cAlkoxyxe2x80x9d means a radical xe2x80x94OR where R is an alkyl group as defined herein e.g., methoxy, ethoxy, propoxy, butoxy, and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d means a radical xe2x80x94C(O)xe2x80x94R where R is alkoxy is as defined herein.
xe2x80x9cAlkylxe2x80x9d means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like.
xe2x80x9cAlkylaminoxe2x80x9d means a radical xe2x80x94NHR where R represents an alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein. Representative examples include, but are not limited to methylamino, ethylamino, 1-methylethylamino, cyclohexylamino, and the like.
xe2x80x9cAlkylenexe2x80x9d means a linear saturated divalent hydrocarbon radical of one to ten carbon atoms or a branched saturated divalent hydrocarbon radical of three to ten carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
xe2x80x9cAlkylsulfonylxe2x80x9d means a radical xe2x80x94S(O)2R where R is an alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein, e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, cyclohexylsulfonyl and the like.
xe2x80x9cAlkylsulfinylxe2x80x9d means a radical xe2x80x94S(O)R where R is an alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, cyclohexylsulfinyl and the like.
xe2x80x9cAlkylthioxe2x80x9d means a radical xe2x80x94SR where R is an alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein e.g., methylthio, ethylthio, propylthio, butylthio, cyclohexylthio and the like.
xe2x80x9cArylxe2x80x9d means a monocyclic or bicyclic aromatic hydrocarbon radical which is optionally substituted with one or more substituents, preferably one, two or three, substituents preferably selected from the group consisting of alkyl, acyl, acylamino, alkoxycarbonyl, alkylamino, alkylsulfinyl, alkylsulfonyl, xe2x80x94SO2NRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl), alkylthio, alkoxy, amino, aryloxy, carbamoyl, cyano, dialkylamino, halo, haloalkyl, heteroalkyl, heterocyclyl, hydroxy, hydroxyalkyl, methylenedioxy, ethylenedioxy, nitro and thio. More specifically the term aryl includes, but is not limited to, phenyl, chlorophenyl, fluorophenyl, methoxyphenyl, 1-naphthyl, 2-naphthyl,and the derivatives thereof.
xe2x80x9cArylalkylxe2x80x9d refers to an alkyl radical as defined herein in which one of the hydrogen atoms of the alkyl group is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
xe2x80x9cAryloxyxe2x80x9d means a radical xe2x80x94Oxe2x80x94R where R is an aryl group as defined herein.
xe2x80x9cArylalkyloxyxe2x80x9d means a radical xe2x80x94Oxe2x80x94R where R is arylalkyl as defined herein.
xe2x80x9cCarbamoylxe2x80x9d means the radical xe2x80x94C(O)N(R)2 where each R group is independently hydrogen, alkyl or aryl as defined herein.
xe2x80x9cCarboxyxe2x80x9d means the radical xe2x80x94C(O)OH.
xe2x80x9cCyanoxe2x80x9d means the radical xe2x80x94CN.
xe2x80x9cCycloalkylxe2x80x9d refers to a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons e.g., cyclopropyl, cyclobutyl, cyclohexyl, 4-methylcyclohexyl and the like.
xe2x80x9cCycloalkyl-alkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a cycloalkyl group as defined herein, e.g., cyclohexylmethyl and the like.
xe2x80x9cCycloalkoxyxe2x80x9d refers to a radical xe2x80x94OR wherein R is a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons e.g., cyclopropyl, cyclobutyl, cyclohexyl, 4-methylcyclohexyl and the like.
xe2x80x9cCycloalkyl-alkyloxyxe2x80x9d means a radical xe2x80x94RaORb where Ra is an alkylene group and Rb is a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons.
xe2x80x9cSubstituted cycloalkylxe2x80x9d means a cycloalkyl radical as defined herein with one, two or three (preferably one) hydrogen atoms replaced by xe2x80x94Yxe2x80x94C(O)R (where, Y is absent or an alkylene group and R is hydrogen, acyl, acylamino, alkyl, alkoxycarbonyl, alkyamino, alkylsulfinyl, alkylsulfonyl, alkylthio, alkoxy, amino, aryloxy, arylalkyloxy, carbamoyl, cyano, dialkylamino, halo, haloalkyl, heteroalkyl, hydroxy, hydroxyalkyl, nitro or thio)
xe2x80x9cDialkylaminoxe2x80x9d means a radical xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 independently represent an alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein. Representative examples include, but are not limited to dimethylamino, methylethylamino, di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)amino, (cyclohexylmethyl)(ethyl)amino and the like.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro.
xe2x80x9cHaloalkylxe2x80x9d means an alkyl group substituted with one or more same or different halo atoms, e.g., xe2x80x94CH2Cl, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CCl3 and the like.
xe2x80x9cHeteroarylxe2x80x9d means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring is optionally substituted independently with one or more substituents, preferably one or two substituents, selected from acyl, acylamino, alkyl, alkoxycarbonyl, alkyamino, alkylsulfinyl, alkylsulfonyl, xe2x80x94SO2NRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl), alkylthio, alkoxy, amino, aryloxy, carbamoyl, cyano, dialkylamino, ethylenedioxy, halo, haloalkyl, heteroalkyl, heterocyclyl, hydroxy, hydroxyalkyl, methylenedioxy, nitro and thio. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl and derivatives thereof.
xe2x80x9cHeteroarylalkyl means an alkyl radical as defined herein in which one of the hydrogen atoms of the alkyl group is replaced with a heteroaryl group.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl radical as defined herein wherein one or more hydrogen atoms have been replaced with a substituent independently selected from the group consisting of xe2x80x94ORa, xe2x80x94NRbRc, and xe2x80x94S(O)nRd (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein Ra is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkyl-alkyl; Rb and Rc are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkyl-alkyl; and when n is 0, Rd is hydrogen, alkyl, cycloalkyl, or cycloalkyl-alkyl, and when n is 1 or 2, Rd is alkyl, cycloalkyl, cycloalkyl-alkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.
xe2x80x9cHeteroalkylaminoxe2x80x9d means a radical xe2x80x94NHR where R is a heteroalkyl group as defined herein.
xe2x80x9cHeteroalkyloxyxe2x80x9d means a radical xe2x80x94Oxe2x80x94R where R is a heteroalkyl group as defined herein.
xe2x80x9cHeteroalkylthioxe2x80x9d means a radical xe2x80x94Sxe2x80x94R where R is a heteroalkyl group as defined herein.
xe2x80x9cHeteroalkylsubsituted cycloalkylxe2x80x9d means a cycloalkyl radical as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been independently replaced with a heteroalkyl group with the understanding that the heteroalkyl radical is attached to the cycloalkyl radical via a carbon-carbon bond. Representative examples include, but are not limited to, 1-hydroxymethylcyclopentyl, 2-hydroxymethylcyclohexyl, and the like.
xe2x80x9cHeterosubstituted cycloalkylxe2x80x9d means a cycloalkyl radical as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a substituent independently selected from the group consisting of hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, oxo (Cxe2x95x90O), imino, hydroximino (xe2x95x90NOH), NRxe2x80x2SO2Rd (where Rxe2x80x2 is hydrogen or alkyl and Rd is alkyl, cycloalkyl, amino, monoalkylamino or dialkylamino), xe2x80x94Xxe2x80x94C(O)R (where X is O or NRxe2x80x2, R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, or optionally substituted phenyl, and Rxe2x80x2 is H or alkyl) or xe2x80x94S(O)nR (where n is an integer from 0 to 2) such that when n is 0, R is hydrogen, alkyl, cycloalkyl, or cycloalkyl-alkyl, and when n is 1 or 2, R is alkyl, cycloalkyl, cycloalkyl-alkyl, amino, acylamino, monoalkylamino or dialkylamino. Representative examples include, but are not limited to, 2-, 3- or 4-hydroxycyclohexyl, 2-, 3- or 4-aminocyclohexyl, 2-, 3- or 4-sulfonamidocyclohexyl, and the like, preferably 4-hydroxycyclohexyl, 2-aminocyclohexyl, 4-sulfonamidocyclohexyl.
xe2x80x9cHeterosubstituted cycloalkyl-alkylxe2x80x9d means a radical RaRbxe2x80x94 where Ra is a heterosubstituted cycloalkyl radical and Rb is an alkylene radical.
xe2x80x9cHeterocyclylxe2x80x9d means a saturated or unsaturated non-aromatic cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocyclyl ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyanoalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, arylalkyl, xe2x80x94(X)nxe2x80x94C(O)R (where, X is O or NRxe2x80x2, n is 0 or 1, R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylaamino, or optionally substituted phenyl and Rxe2x80x2 is H or alkyl), -alkylene-C(O)R (where R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino or optionally substituted phenyl) or xe2x80x94S(O)nRd (where n is an integer from 0 to 2, and Rd is hydrogen (provided that n is 0), alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, amino, monoalkylamino, dialkylamino, or hydroxyalkyl). More specifically the term heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, pyrrolinyl, imidazolinyl, and the derivatives thereof.
xe2x80x9cHeterocyclylalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a heterocyclyl group as defined above, e.g., tetrahydropyran-2-ylmethyl, 1,2-, or 3-piperidinylmethyl, 1-piperazinylmethyl, 4-methyl-piperazin-1-ylmethyl, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means an alkyl radical as defined herein, substituted with one or more hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl. Accordingly, as used herein, the term xe2x80x9chydroxyalkylxe2x80x9d is used to define a subset of heteroalkyl groups.
xe2x80x9cLeaving groupxe2x80x9d has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or a group capable of being displaced by a nucleophile and includes halo (such as chloro, bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamino, and the like.
xe2x80x9cOxoxe2x80x9d means divalent radical (Cxe2x95x90O).
xe2x80x9cPharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d as used in the specification and claims includes both one and more than one such excipient.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
The terms xe2x80x9cpro-drugxe2x80x9d and xe2x80x9cprodrugxe2x80x9d are used interchangeably herein and refer to any compound which releases an active parent drug according to structural formula (I-VII) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of structural formula (I-VII) are prepared by modifying one or more functional group(s) present in the compound of structural formula (I-VII) in such a way that the modification(s) may be cleaved in vivo to release the parent compound. Prodrugs include compounds of structural formula (I-VII) wherein a hydroxy, amino, or sulfhydryl group in a compound of structural formula (I-VII) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of structural formula (I-VIII), N-acyl derivatives (e.g. N-acetyl) N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of Formula I-VII, and the like, see Bundegaard, H. xe2x80x9cDesign of Prodrugsxe2x80x9d p1-92, Elesevier, New York-Oxford (1985), and the like.
xe2x80x9cProtecting groupxe2x80x9d refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in T. W. Green and P. G. Futs, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, (Wiley, 2nd ed. 1991) and Harrison et al., xe2x80x9cCompendium of Synthetic Organic Methodsxe2x80x9d, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC) and the like. Representative hydroxy protecting groups include but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
As used herein, the term xe2x80x9cmammalxe2x80x9d includes human. The terms xe2x80x9chumanxe2x80x9d and xe2x80x9cpatientxe2x80x9d are used interchangeably herein.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of emphysema, cancer or a dermatological disorder includes preventing the disease, (i.e., causing at least one of the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease) inhibiting the disease (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms) or relieving the disease, (i.e., causing regression of the disease or at least one of the clinical symptoms). Preventing or prevention encompasses administration administration prior to manifestation of the disease or disorder.
xe2x80x9cA therapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
Reference will now be made in detail to preferred embodiments of the invention. While the invention will be described in conjunction with preferred embodiments, it should be understood that it is not intended to limit the invention to these preferred embodiments. To the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.
The present invention encompasses novel retinoid compounds and their uses to effectively treat emphysema, cancer and dermatological disorders. The invention encompasses treating emphysema and related disorders, cancer and dermatological disorders, preferably while reducing or avoiding adverse effects associated with natural and synthetic retinoids when used at therapeutic levels. Adverse effects associated with retinoids at therapeutic levels include, but are not limited to, the toxic effects of hypervitaminosis A, such as headache, fever, skin and membrane dryness, bone pain, nausea and vomiting, psychiatric disorders and gastrointestinal disorders.
In one embodiment, the present invention provides compounds having the structural formula (I): 
or a pharmaceutically acceptable salt, solvate or hydrate thereof wherein:
n is an integer from 0 to 2;
c is 0 or 1;
d is 0 or 1;
A is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90CH2)xe2x80x94, xe2x80x94C(xe2x95x90NR4)xe2x80x94 or xe2x80x94CR5R6xe2x80x94;
R4 is hydrogen,alkyl, hydroxy, alkoxy or amino; and
R5 and R6 are independently hydrogen, alkyl or together, along with the carbon to which they are both attached, are cycloalkyl;
B is xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHC(O)NHxe2x80x94, xe2x80x94CR7xe2x95x90CR8xe2x80x94, xe2x80x94R7Cxe2x95x90CR8xe2x80x94C(O)xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94C(O)xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94COCH2xe2x80x94, or xe2x80x94CH2COxe2x80x94;
R7 and R8 are independently hydrogen or alkyl;
with the provisos that:
when A is xe2x80x94C(xe2x95x90O)xe2x80x94, or xe2x80x94C(xe2x95x90NR4)xe2x80x94, then B is not xe2x80x94OC(O)xe2x80x94; and
when A is xe2x80x94C(xe2x95x90CH2)xe2x80x94, then B is not xe2x80x94OC(O)xe2x80x94;
X is aryl or heteroaryl;
R1 is xe2x80x94C(xe2x95x90O)xe2x80x94R9;
R9 is alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, aryloxy, cycloalkyloxy, cycloalkyl-alklyloxy, arylalkyloxy, amino, alkylamino, dialkylamino, heteroalkyloxy, heteroalkylamino, heteoalkylthio, heterocyclyl or heterocyclylalkyl; and
R2 is:
(a) xe2x80x94(CR10R11)mxe2x80x94Ypxe2x80x94R12;
m is an integer from 1 to 10;
p is 0 or 1;
R10 and R11 are independently hydrogen, alkyl, hydroxy or hydroxyalkyl;
Y is xe2x80x94Oxe2x80x94, xe2x80x94S(O)qxe2x80x94 or xe2x80x94NR13xe2x80x94; and
q is an integer from 0 to 2; and
R13 is hydrogen or alkyl;
R12 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxycarbonyl, carbamoyl, substituted cycloalkyl, heteroalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heterosubstituted cycloalkyl-alkyl, heterocyclyl or heterocyclylalkyl;
with the proviso that when p=0, then R12 is not hydrogen or alkyl;
(b) heteroaryl;
(c) xe2x80x94Zxe2x80x94L; where:
Z is xe2x80x94CR14xe2x95x90CR15xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR16xe2x80x94, C(xe2x95x90O) or xe2x80x94S(O)qxe2x80x94;
R14, R15 and R16 are independently hydrogen or alkyl; and
L is heteroaryl, heteroarylalkyl or heteroalkyl;
with the proviso that when Acxe2x80x94Bd is xe2x80x94C(xe2x95x90O)xe2x80x94CR7xe2x95x90CR8xe2x80x94, then L is not heteroalkyl; or
(d) xe2x80x94CR14xe2x95x90CR15xe2x80x94L1 where L1 is S(O)2R17 or SO2NR18R19 where R17 is alkyl and R18 and R19 are independently hydrogen or alkyl;
each R3 is independently hydrogen, alkyl, hydroxy or oxo; and
t is 1 or 2.
Preferred compounds of the invention are RAR agonists, particularly RAR-gamma selective agonists and bind to the RAR-gamma receptor at least five fold better than they bind to the RAR-alpha receptor. Binding affinities for RAR agonists are typically less than 10 micromolar, preferably less than 1 micromolar.
In one embodiment, n is 1. In another embodiment, A is xe2x80x94C(xe2x95x90O)xe2x80x94. In yet another embodiment, c is 0.
Preferably, B is xe2x80x94NHC(O)NHxe2x80x94, xe2x80x94CR7xe2x95x90CR8xe2x80x94, xe2x80x94R7Cxe2x95x90CR8xe2x80x94C(O)xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94C(O)xe2x80x94 or xe2x80x94CH2Oxe2x80x94, most preferably xe2x80x94CR7xe2x95x90CR8xe2x80x94, and particularly R7 and R8 are hydrogen where B is trans xe2x80x94CHxe2x95x90CHxe2x80x94, i.e., the alkene moiety has the E-stereochemistry.
In one embodiment, X is phenyl. In another embodiment, X is thienyl. In one embodiment, R3 is hydrogen. In another embodiment, R3 is hydroxy or oxo. In one embodiment, R9 is alkoxy, aryloxy or arylalkyloxy. In another embodiment, R9 is hydroxy.
In one preferred embodiment, the invention provides compounds having structural formula (II): 
or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein A, B, c, d, X, R1, R3, n, R10, R11, m, Y, p and R12 are as previously defined. Preferably, m is 1 to 4. In one embodiment, p is 0. In another embodiment, p is 1.
In a preferred embodiment of compounds having structural formula (II), m is 1, p is 1 and Y is xe2x80x94Oxe2x80x94. Preferably, R12 is hydrogen, acyl, alkyl, carbamoyl, cycloalkyl, aryl, heteroaryl, or heteroalkyl. Compounds 1, 5 and 15 in Table 10 exemplify this embodiment.
In another preferred embodiment of compounds having structural formula (II), m is 1, p is 1 and Y is xe2x80x94S(O)qxe2x80x94. In one embodiment, R12 is alkyl, cycloalkyl or heteroalkyl. Compounds 2, 3, 4, 9, 17 and 18 in Table 1 exemplify this embodiment. In another embodiment, R12 is heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl. Compounds 8, 19, 22, 23, 25, 32, 34 and 35 in Table 1 exemplify this embodiment.
In still another preferred embodiment of compounds having structural formula (II), m is 3, p is 1 and Y is xe2x80x94Oxe2x80x94. Preferably, R12 is hydrogen, acyl, alkyl, carbamoyl, cycloalkyl, aryl, heteroaryl, or heteroalkyl. Compounds 10, 11 and 12 in Table 1 exemplify this embodiment.
In still another preferred embodiment of compounds having structural formula (II), m is 3, p is 1 and Y is xe2x80x94NR13xe2x80x94. Preferably, R12 is acyl, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl. Compound 33 in Table 1 exemplifies this embodiment.
In still another preferred embodiment of compounds having structural formula (II), m is 3, p is 1 and Y is xe2x80x94S(O)qxe2x80x94. Preferably, R12 is aryl, arylalkyl, heteroaryl, heteroalkyl, heterocyclyl or heterocyclylalkyl. Compounds 24 and 28 in Table 1 exemplify this embodiment.
In still another preferred embodiment of compounds having structural formula (II), m is 2, p is 1 and Y is xe2x80x94Oxe2x80x94. Preferably, R12 is hydrogen, acyl, alkyl, carbamoyl, cycloalkyl, aryl, heteroaryl, or heteroalkyl. Compound 31 in Table 1 exemplifies this embodiment.
In still another preferred embodiment of compounds having structural formula (II), m is 2, p is 1 and Y is xe2x80x94S(O)qxe2x80x94. Preferably, R12 is aryl, arylalkyl, heteroaryl, heteroalkyl, heterocyclyl or heterocyclylalkyl. Compounds 26 and 27 in Table 1 exemplify this embodiment.
In still another preferred embodiment of compounds having structural formula (II), m is 4, p is 1 and Y is xe2x80x94(O)xe2x80x94. Preferably, R12 is hydrogen, acyl, alkyl, carbamoyl, cycloalkyl, aryl, heteroaryl, or heteroalkyl. Compound 51 in Table 1 exemplifies this embodiment.
In still another preferred embodiment of compounds having structural formula (II), m is 1 and p is 0. In one embodiment, R12 is heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl. Compounds 6, 7, 44, 45, 47, 50, 53, 54, 55, 138, 139, 143, 146,149 and 150 in Table 1 exemplify this embodiment. Compound 6 is a particularly preferred member of the above group of compounds. In another embodiment, R12 is aryl, arylalkyl, cycloalkyl or substituted cycloalkyl. Compounds 42 and 54 in Table 1 exemplify this embodiment.
In still another preferred embodiment of compounds having structural formula (II), m is 2 and p is 0. Preferably, R12 is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroalkyl, heterocyclyl or heterocyclylalkyl. Compounds 29, 37, 38, 40, 41, 132, 134, 140, 147 and 152 in Table 1 exemplify this embodiment.
In still another preferred embodiment of compounds having structural formula (II), m is 3 and p is 0. Preferably, R12 is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl. Compounds 30, 36, 46, 52, 130, 131, 135, 141 and 142 in Table 1 exemplify this embodiment.
In another preferred embodiment, the invention provides compounds having the structural formula (III): 
or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein A, B, c, d, X, R1, R3 and n are as previously defined. Compounds 48, 49, 156 and 157 in Table 1 exemplify the preceding embodiment.
In another embodiment, the invention provides compounds having structural formula (IV): 
or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein A, B, c, d, X, R1, R3, n, Z and L are as previously defined. In one embodiment, L is heteroaryl or heteroarylalkyl. In another embodiment, Z is xe2x80x94Oxe2x80x94 or xe2x80x94S(O)qxe2x80x94. Compounds 154, 155, 159 and 160 in Table 1 exemplify this embodiment.
In another embodiment of generic formula (I), c is 0, d is 1 and B is xe2x80x94CR7xe2x95x90CR8xe2x80x94 and n, R1, R2 R3 and X are as previously defined. Preferably, R7 and R8 are both hydrogen. In one embodiment, X is aryl. In a more specific embodiment, the invention provides compounds having the structural formula (V): 
or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein n, R1, R2 and R3 are as previously defined. In another embodiment, the invention provides compounds having the structural formula (VI): 
or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein n, R1, R2 and R3 are as previously defined.
In another embodiment, X is heteroaryl. In this embodiment, the invention provides compounds having the structural formula (VII): 
or a pharmaceutically acceptable salt, solvate or hydrate, thereof, wherein n, R1, R2 and R3 are as previously defined.
Another embodiment of this invention is represented by compounds of structural formula VIII, 
wherein:
R20 is alkyl;
R21 is: (a) heteroalkyloxy, heteroalkylamino, or heteroalkylthio; or
(b) Qxe2x80x94R22 where Q is xe2x80x94Oxe2x80x94, xe2x80x94NR23xe2x80x94 or xe2x80x94Sxe2x80x94 (where R23 is hydrogen or alkyl) and
R22 is carboxyalkyl;
and n is an integer from 0 to 2.
These compounds are prodrugs of compounds of Formula VIII where R21 is hydroxy and are converted in vivo to compounds where R21 is hydroxy. Compounds 56, 57, 58 and 59 exemplify this embodiment.
Preferred compounds of the invention include those depicted in Table 1 below.
Another aspect of the invention encompasses a method of treating emphysema in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the invention, or pro-drug thereof. In one embodiment, the emphysema is panlobar emphysema, centrilobular emphysema or distal emphysema.
Preferably, the therapeutically effective amount of a compound of the invention or pro-drug thereof, for treating emphysema, is between about 0.1 xcexcg/qd and about 30.0 mg/qd, more preferably between about 1.0 xcexcg/qd and about 1.0 mg/qd. In one embodiment, especially for oral administration, the therapeutically effective amount of a compound of the invention or pro-drug thereof is between about 10.0 xcexcg/qd and about 30 mg/qd, preferably 30.0 xcexcg/qd to about 300.0 xcexcg/qd. In another embodiment, especially for administration by inhalation, the therapeutically effective amount of a compound of the invention or pro-drug thereof, is between about 0.1 xcexcg/qd and about 100.0 xcexcg/qd, more preferably between about 10.0 xcexcg/qd and about 100.0 xcexcg/qd, most preferably between about 1.0 xcexcg/qd and about 30.0 xcexcg/qd.
This aspect of the invention encompasses a method of treating emphysema in a mammal by repairing alveoli in a mammal. In a preferred embodiment, the mammal is human. Preferably, the human was or is a cigarette smoker. In another preferred embodiment, an electrohydrodynamic aerosol device or a nebulizer device or an aerosol device is used to administer the therapeutically effective amount of a compound of the invention, or pro-drug thereof.
Another aspect of the invention encompasses a pharmaceutical composition for the treatment of a mammal suffering from emphysema comprising an amount of a compound of the invention or pro-drug thereof in a pharmaceutically acceptable carrier, with the amount of the compound being sufficient to alleviate one symptom of emphysema. In one embodiment, the emphysema is panlobar emphysema, centrilobular emphysema or distal emphysema. In a preferred embodiment, the mammal is human. Preferably, the human was or is a cigarette smoker.
The major symptoms of emphysema include but are not limited to chronic shortness of breath, chronic cough, coloration of the skin caused by lack of oxygen, shortness of breath with minimal physical activity and wheezing. Additional symptoms that may be associated with emphysema include, but are not limited to vision abnormalities, dizziness, temporary cessation of respiration, anxiety, swelling, fatigue, insomnia and memory loss.
Preferably, the amount of a compound of the invention or pro-drug thereof, in the pharmaceutical composition, is between about 0.1 xcexcg and about 30.0 mg, more preferably between about 1.0 xcexcg and about 1.0 mg, most preferably between about 100.0 xcexcg and about 300.0 xcexcg.
In one embodiment, the pharmaceutically acceptable carrier is suitable for an electrohydrodynamic aerosol device, a nebulizer device or a aerosol device. In one preferred embodiment, the pharmaceutically acceptable carrier is a liquid such as water, alcohol, polyethylene glycol or perfluorocarbon. The amount of a compound of the invention, or pro-drug thereof in the pharmaceutical composition in this preferred embodiment is between about 0.1 xcexcg and about 1.0 mg, more preferably between about 1.0 xcexcg and about 100.0 xcexcg, most preferably between about 50.0 xcexcg and about 150.0 xcexcg.
Another aspect of the invention encompasses a method for treating emphysema and related disorders by delivering a formulation of a compound of the invention or pro-drug thereof, into the lungs of a mammal. Preferably, the mammal is a human, more preferably, the human was or is a cigarette smoker. In one embodiment, the formulation is delivered into the lungs of the mammal with a nebulizer device. In a second embodiment, the formulation is delivered into the lungs of the mammal with an aerosol device. In a third embodiment, the formulation is delivered into the lungs of the mammal with an electrohydrodynamic aerosol device.
In an exemplary embodiment, the formulation is a pharmaceutical composition of a compound of the invention. Preferably, the amount of a compound of the invention, or pharmaceutically acceptable salt, hydrate, solvate, or pro-drug thereof in the pharmaceutical composition is between about 1.0 xcexcg and about 10.0 mg, more preferably between about 10.0 xcexcg and about 1.0 mg, most preferably between about 50.0 xcexcg and about 150.0 xcexcg. In one preferred embodiment, the pharmaceutically acceptable vehicle is a liquid such as water, alcohol, polyethylene glycol or perfluorocarbon. In another preferred embodiment, a material that alters the aerosol properties of the formulation is added to the formulation. Preferably, the material is an alcohol, glycol, polyglycol or fatty acid.
In still another aspect, the present invention encompasses a method for treating emphysema that combines use of a compound of the invention with one or more additional therapies. The additional therapies include, but are not limited to, smoking cessation, antibiotics, bronchodilators and oxygen therapy. In a preferred embodiment, a pharmaceutical composition of a compound of the invention is used in combination with other therapies.
In a still another aspect, the current invention provides a method for preventing emphysema in a human at risk of emphysema by administering a amount of a compound of the invention or pro-drug thereof, sufficient to prevent emphysema. In a preferred embodiment, the human was or is a cigarette smoker.
In another aspect, the present invention provides a pharmaceutical composition that prevents emphysema in a human at risk of emphysema. The composition comprises an amount of a compound of the invention or pro-drug thereof, and a pharmaceutically acceptable carrier that is sufficient to prevent emphysema.
Another aspect of the invention encompasses a method of treating cancer in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the invention or pro-drug thereof. Preferably, the cancer is of epithelial origin and includes, but is not limited to breast cancer, skin cancer, colon cancer, stomach tumors, laryngeal cancer and lung cancer.
Preferably, the therapeutically effective amount of a compound of the invention or pro-drug thereof for treating cancer, is between about 50 xcexcg/qd and about 500 mg/qd, more preferably between about 300 xcexcg/qd and about 30 mg/qd. In one embodiment, especially for oral administration, the therapeutically effective amount of a compound of the invention or pro-drug thereof is between about 3 mg/qd and about 120 mg/qd. In another embodiment, especially for administration by inhalation, the therapeutically effective amount of a compound of the invention or pro-drug thereof, is between about 50 xcexcg/qd and about 500 xcexcg/qd , more preferably between about 50 xcexcg/qd and about 150 xcexcg/qd.
In a preferred embodiment, the mammal is human. In another preferred embodiment, a electrohydrodynamic aerosol device or a nebulizer device or a aerosol device is used to administer the therapeutically effective amount of a compound of the invention or pro-drug thereof.
Another aspect of the invention encompasses a pharmaceutical composition for the treatment of a mammal suffering from cancer comprising an amount of a compound of the invention or pro-drug thereof in a pharmaceutically acceptable carrier, with the amount of the compound being sufficient to alleviate one symptom of cancer. Preferably, the cancer is of epithelial origin and includes, but is not limited to breast cancer, skin cancer, colon cancer, stomach tumors, laryngeal cancer and lung cancer. In a preferred embodiment, the mammal is human.
Preferably, the amount of a compound of the invention or pro-drug thereof, in the pharmaceutical composition, is between about 250 xcexcg and about 500 mg, more preferably between about 2.5 mg and about 100 mg, most preferably between about 10 mg and about 50 mg.
In one embodiment, the pharmaceutically acceptable carrier is suitable for a electrohydrodynamic aerosol device, a nebulizer device or a aerosol device. In one preferred embodiment, the pharmaceutically acceptable carrier is a liquid such as water, alcohol, polyethylene glycol or perfluorocarbon. The amount of a compound of the invention or pro-drug thereof, in the pharmaceutical composition in this preferred embodiment is between about 50 xcexcg and about 1.5 mg, more preferably between about 150 xcexcg and about 1.5 mg, most preferably between about 150 xcexcg and about 300 xcexcg.
Another aspect of the invention encompasses a method for treating cancer by delivering a formulation of a compound of the invention or pro-drug thereof, into the lungs of a mammal. Preferably, the mammal is a human, more preferably, the human has lung cancer. In one embodiment, the formulation is delivered into the lungs of the mammal with a nebulizer device. In a second embodiment, the formulation is delivered into the lungs of the mammal with an aerosol device. In a third embodiment, the formulation is delivered into the lungs of the mammal with an electrohydrodynamic aerosol device.
In an exemplary embodiment, the formulation is a pharmaceutical composition of a compound of the invention. Preferably, the amount of a compound of the invention or pro-drug thereof, in the pharmaceutical composition is between about 50 xcexcg and about 1.5 mg, more preferably between about 50 xcexcg and about 1.5 xcexcg, most preferably between about 100 xcexcg and about 300 xcexcg. In one preferred embodiment, the pharmaceutically acceptable vehicle is a liquid such as water, alcohol, polyethylene glycol or perfluorocarbon. In another preferred embodiment, a material that alters the aerosol properties of the formulation is added to the formulation. Preferably, the material is an alcohol, glycol, polyglycol or fatty acid.
In still another aspect, the present invention encompasses a method for treating cancer that combines use of a compound of the invention with one or more additional therapies. The additional therapies include, but are not limited to, chemotherapy, radiation or surgery. In a preferred embodiment, a pharmaceutical composition of a compound of the invention is used in combination with other therapies.
In a still another aspect, the current invention provides a method for preventing cancer in a human at risk of cancer (e.g., smokers, asbestos workers and uranium workers) by administering a amount of a compound of the invention or pro-drug thereof, sufficient to prevent cancer. Examples of premalignant and precancerous lesions or tumors which may be prevented by compounds of the invention include, but are not limited to, actinic and arsenic keratoses, dysplasias and papillomas of mucous membranes and precancerous changes of the bladder.
Another aspect of the present invention provides a pharmaceutical composition that prevents cancer in a human at risk of cancer. The composition comprises an amount of a compound of the invention or pro-drug thereof, and a pharmaceutically acceptable carrier that is sufficient to prevent cancer.
Another aspect of the invention encompasses a method of treating dermatological disorders in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the invention or pro-drug thereof. Preferably, the dermatological disorders include, but are not limited to, damage to the skin caused by light and age, surgical wounds, burn wounds, wounds caused by cutaneous trauma, acne and psoriasis.
Preferably, the therapeutically effective amount of a compound of the invention or pro-drug thereof for treating dermatological disorders, is between about 5 xcexcg/qd and about 50 mg/qd, more preferably between about 50 xcexcg/qd and about 5 mg/qd. Topical (skin) emollients typically are creams, lotions or ointments containing from about 1% to 0.005%, preferably 0.5% to 0.01%, most preferably 0.05% to 0.01%.
The compounds of the invention having formulas (I-VII) may be obtained via the synthetic methodology illustrated in Schemes 1-7 and methods described in the art (Douget et al., Quant. Struct. Act. Relat., 18, 107, (1999) and references disclosed therein, which are herein incorporated by reference). Starting materials useful for preparing compounds of the invention and intermediates thereof are commercially available or can be prepared by well known synthetic methods. 
Compounds 67 of formula (I) where n=0, 1 or 2, m is 1 and R is alkoxy, alkylthio, heteroaryl, heterocyclyl, amino, alkylamino etc. may be prepared as described in Scheme 1. Bromo substituted 5,5,8,8-tetramethyl-5,6,7,8 tetrahydronapthalenes 62 and the corresponding five and seven member ring analogues may be synthesized by a number of methods known to the skilled artisan. In a preferred embodiment, Friedel-Crafts alkylation of 2-bromotoluene 61 with 2,4-dichloro-2,4-dimethylpentane, 2,5-dichloro-2,5-dimethylhexane or 2,6-dichloro-2,6-dimethylheptane 60 provides compounds 62. Aryl bromides 62 may be homologated to aldehydes 64 by halogen-metal exchange (i.e., n-butyl lithium) to form an intermediate organolithium compound, which is then quenched with N-formylpiperidine. Alternatively, aldehydes 63 may be made by homologation of bromides 62 (i.e., Cu(I)CN) to a cyano compound which may reduced (i.e., diisobutyl aluminum hydride). Other synthetic methods for effecting conversion of bromides 62 to aldehydes 63 will be apparent to the skilled artisan.
Horner-Emmons olefination of aldehydes 63 with an appropriate phosphonate ester may be used to provide E olefins 64. Corresponding Z olefins may be prepared by conventional Wittig reactions followed by separation if necessary. Bromination of compounds 64 (i.e., N-bromosuccinimide, benzoyl peroxide and light) affords the benzyl bromides 65. The bromides may be displaced with nitrogen, sulfur or oxygen nucleophiles to yield the corresponding substituted esters 66 which may be hydrolyzed (acid or base) to provide the acids 67. Acids 67 may be esterified using well known methods to provide a large number of esters. 
Compounds 78 of formula (I) where n=0, 1 or 2, m is 2-10 and R12 is alkoxy, alkylthio, heteroaryl, heterocyclyl, amino, alkylamino etc. may be prepared as described in Scheme 2. Hydroxyalkyl substituted 5,5,8,8-5,6,7,8 tetrahydronapthalenes 69 are readily accessible by Friedel-Crafts reaction of 2,4-dichloro-2,4-dimethylpentane, 2,5-dichloro-2,5-dimethylhexane or 2,6-dichloro-2,6-dimethylheptane 60 with hydroxyalkylbenzenes 68. Bromination of hydroxyalkyl-5,5,8,8-5,6,7,8 tetrahydronapthalenes 69 affords aryl bromides 70. The hydroxyl group of 70 can be protected (i.e., t-butyldimethylsilyl chloride and imidazole) to provide compounds 71. Bromides 71 can be converted to aldehydes 72 in one step (i.e., halogen-metal exchange with n-butyl lithium, followed by treatment with N-formylpiperidine). Alternatively, aldehydes 72 may be made from bromides 70 by a two step procedure (i.e., Cu(I)CN to provide a nitrile and reduction with di-isobutyl aluminum hydride). Other methods for effecting conversion of bromides 70 to aldehydes 72 are within the capability of those of skill in the art.
Horner-Emmons olefination of aldehydes 72 with an appropriate phosphonate ester may be used to provide E olefins 74. The protecting group may be removed from compounds 74 (i.e., aqueous tetrabutyl ammonium fluoride) to provide alcohols 76. In a preferred embodiment, alcohols 76 may be converted by Mitsonobu reaction, (i.e., alkylthiols, triphenylphosphine and diisopropyl azodicarboxylate) to thiol analogs 78 (R=alkylthio). Alternatively, the hydroxyl functionality of compounds 76 may be activated by conversion to the mesylate (MsCl, Et3N) followed by displacement reactions with nitrogen or oxygen nucleophiles to provide compounds 78 (R=alkoxy, amino, alkylamino, dialkyamino etc.). Other methods for effecting conversion of alcohols 76 to compounds of the invention are known to the skilled artisan. Ester hydrolysis may be used to provide the free acids of compounds 78. 
For compounds of formula I, where m=2, an alternative method is depicted in Scheme 3. Bromo substituted 5,5,8,8-tetramethyl-5,6,7,8 tetrahydronapthalenes 62 described in Scheme 1 may converted to bromoaldehydes 82 by benzylic bromination with N-bromosuccinimide and benzoyl peroxide to afford 80, followed by treatment with 2-nitropropane and sodium hydride. Treatment of bromoaldehyde 82 with trimethylsilylacetylene, dichlorobis(triphenylphosphine)palladium (II), cuprous iodide and triethylamine afforded silyated acetylene compounds 84. Removal of the trimethylsilyl group with base provides 86 which is followed by reaction with halogenatedheteroaromatics, dichlorobis(triphenylphosphine) palladium (II), cuprous iodide and triethylamine to yield acetylenic heteroaromatic intermediates 88. Catalytic hydrogenation of acetylenes 88 afforded the saturated heteroaromatic intermediates 90. Horner-Emmons olefination of 90 with the appropriate phosphonate ester yields E olefins 92. The ester may then be hydrolyzed to provide retinoid analogs 94. 
For compounds of Formula 1 where Z=acetylene and L=heteroaryl, as shown in Scheme 3b, intermediate 88 may be treated under Horner-Emmons olefination conditions with the appropriate phosphonate to give E olefins and subsequently hydrolyzed to provide retinoid analogs 81.
For compounds of Formula 1 where Z=olefin and L=heteroaryl, intermediate 82 may be treated with trans-1,2-bis (tri-n-butylstannyl)ethylene and tetrakis (triphenylphosphine)palladium in toluene under reflux, followed by addition of halo heteroaromatics to afford olefin 83. Horner-Emmons olefination of 83 with the appropriate phosphonate ester followed by hydrolysis provides retinoid analogs 85. Alternatively for R2=vinylsulfone, treatment of intermediate 82 with methyl vinyl sulfone, tetrakis(triphenylphosphine)palladium and TEA in DMF affords vinyl sulfone intermediate 87. Olefination, followed by hydrolysis provides retinoid analogs 89. Alternatively for R2=vinylsulfonamide, treatment of intermediate 82 with tert-butyl[diphenylphosphoryl)methyl]sulfonylcarbamate and NaH in DMF affords vinylsulfonamide intermediate 91. Treatment of 91 with tributylstannylmethane and tetrakis(triphenyl phosphine) palladium in dioxane gave hydroxymethyl intermediate 93. Oxidation of 93 with 1,1,1-triacetoxy-1,1,1-1,1-dihydro-1,2-benziiodoxol-3(1H)-one, affords aldehyde 95 and olefination, followed by hydrolysis gives retinoid analog 97. 
Compounds 108 where R is a nitrogen-heteroaromatic, with nitrogen directly attached to the aromatic ring or a thio-heteroaromatic, with sulfur directly attached to the aromatic ring may be prepared by the method depicted in Scheme 4. Fluoro substituted 5,5,8,8-teteramethyl-5,6,7,8-tetrahydronaphthalenes 98 can be prepared by Friedel-Crafts reaction of 2,3-dichloro-2,5-dimethylhexane with 2-fluorotoluene 96. Fluoro aldehydes 102 may be made by benzylic bromination of 98 with N-bromosuccinimide and benzoyl peroxide to give 100, followed by treatment of bromide 100 with the anion of 2-nitropropane. Direct displacement of the fluoro group of 102 with a nitrogen heteroaromatic molecule under basic conditions (potassium carbonate) in an aprotic solvent with heating, affords intermediates 104. Horner-Emmons olefination of 104 provides ester intermediates 106 and ester hydrolysis yields products 108 with an aromatic ring substituted with a nitrogen heteroaromatic.
Alternatively, treatment of thio-heteroaromatics with sodium hydride in a polar aprotic solvent followed by addition of fluoroaldehyde 102 afforded intermediates 104 with a thioheteroaromatic group directly attached to the aromatic ring. As before, Horner-Emmons olefination of 104 provided ester intermediate 106 followed by ester hydrolysis to afford products 108 with an aromatic ring substituted with a sulfur heteroaromatic. 
Compounds 116 where m is 1 and R12 is a heteroaryl group linked through carbon or an aryl group can be prepared according to the method depicted in Scheme 5. Bromoaldehyde intermediates 84, previously described, can be protected as acetals 110. Treatment of 110 with an organometallic reagent such as n-BuLi, followed by addition of heteroaryl aldehydes affords alcohols 112. Catalytic hydrogenolysis with noble metal catalysts in the presence of hydrogen removes both the hydroxyl group and the acetal protecting group to provide aldehyde 114. Horner-Emmons olefination with an appropriate phosphonate ester followed by ester hydrolysis provides compound 116.
Alternatively, treatment of 84 with an aryl zinc reagent under palladium catalysis affords aldehyde 114 where R is substituted aryl, after removal of the acetal under acidic conditions. Horner-Emmons olefination of 114 with an appropriate phosphonate ester followed by ester hydrolysis provides compound 116.
Alternatively, dibromo intermediate 80 may be treated with NaCN, followed by reaction with an organometallic heteroaromatic reagent to give 111. Hydrolysis of 111 to the corresponding acid, followed by decarboxylation gives intermediate 113. Double Heck reaction, first with trimethoxyvinlysilane and then with methyl-4-bromobenzoate, followed by hydrolysis gives retinoid analogs 116. 
Compounds 120 where R12 is a heteroaryl group or an aryl group directly attached to the aromatic ring of the tetrahydronapthalene can be prepared according to the method depicted in Scheme 6. Horner-Emmons olefination of 84 with an appropriate phosphonate ester provides bromide 118. Treatment of 118 with heteroaryl boronates or aryl boronates in the presence of palladium catalyst affords the respective heteroaryl substituted analogs or aryl substituted analogues, which upon ester hydrolysis gives compounds 120 with an heteroaryl group or an aryl group directly attached to the aromatic ring. 
Compounds of formula I where R3 is hydroxy may be prepared as exemplified in Schemes 7 and 8. Tetralone 122 may be prepared by condensation of dihydro-2,2,5,5 tetramethyl-3(2H) furanone with toluene. Reduction and protection using standard reagents provides acteate 124. Bis-palladium cross coupling using 4-bromo-ethyl-benzoate and trimethoxyvinylsilane provides compound 126, which may be converted to bromide 128 by free radical bromination. Bromide 128 may be directly displaced with an appropriate nucleophile to provide compounds where m=1 or may be homologated with appropriate carbon nucleophiles to provide compounds where m is greater than 1. 
Alternatively, compounds of formula I where R3 is hydroxy may be prepared as exemplified in Scheme 8. Intermediate acetate 124 can be brominated to prepare 166, followed by treatment with the anion prepared from 2-nitropropane to afford aldehyde 168. Horner-Emmons olefination provides compound 170 and Stille coupling with hydroxymethyltributyltin affords 172. NBS bromination of 172 affords bromide 174. Bromide 174 may be directly displaced with an appropriate nucleophile to provide compounds where m=1 or may be homologated with appropriate carbon nucleophiles to provide compounds where m is greater than 1. 
Compounds of formula I where R3 is oxo may be prepared as exemplified in Schemes 9 and 10. Acetate ester 126 is cleaved under basic conditions and then reesterified to give 176 using trimethysilyldiazomethane. Oxidation of 176 with Dess-Martin reagent affords ketone 178, which may be converted to bromide 180 by free radical bromination. Bromide 180 may be directly displaced with an appropriate nucleophile to provide compounds where m=1 or may be homologated with appropriate carbon nucleophiles where m is greater than 1. 
Alternatively, compounds of formula I where R3 is oxo may be prepared as exemplified in Scheme 10. Aldehyde 168 can be protected as acetal 182 by treatment with ethylene glycol under acidic catalysis and the acetate cleaved under basic conditions to give alcohol 184. Oxidation with Dess-Martin reagent provides ketone 186 and acetal cleavage under acidic conditions gives aldehyde 188. Horner-Emmons olefination with the appropriate phosphonate provides 190 and Stille coupling with hydroxymethyltributyltin affords 192. NBS bromination provides bromide 194, which may be directly displaced with an appropritate nucleophile to provide compounds where m=1 or may be homologated with appropriate carbon nucleophiles to provide compounds where m is greater than 1. 
Compounds of formula I where R3 is a diol may be prepared as exemplified in Schemes 11 and 12. Saponification of acetate intermediate 124 under basic conditions gives alcohol 196 and dehydration upon treatment with POCl3 and pyridine provides olefin 198. Epoxidation of 198 with MCPBA affords 200. The epoxide can be open opened under acidic conditions to give the trans acetate diols which can then be hydrolysed under basic conditions to give the trans diol 202. Protection of the diol as the dimethyl ketal 204 using 2,2 dimethoxypropame under acidic conditions is followed by conversion to aldehyde 206 by treatment with n-butyl lithium and N-formyl piperidine. Horner-Emmons olefination of aldehyde 206 with the appropriate phosphonate gives 208, which may be converted to bromide 210 by free radical bromination. Bromide 210 may be directly displaced with an appropriate nucleophile to provide compounds where m=1 or may be homologated with appropriated carbon nucleophiles to provide compounds where m is greater than 1. 
Alternatively, compounds of formula I where R3 is a diol may be prepared as exemplified in Scheme 12. Olefin 198 can be treated with osmium tetroxide to afford the cis diol 212. Protection of 212 as ketal 214 was followed by conversion to aldehyde 216 by sequential treatment with n-butyl lithium and N-formylpiperidine. Horner-Emmons olefination with the appropriated phosphonate provided 218 and deprotection was followed by reprotection to the bis-acetate 220 with acetic anhydride in pyridine. Free radical bromination of 220 gives bromide 222 which may be directly displaced with an appropriate nucleophile to provide compounds where m=1 or may be homologated with appropriate carbon nucleophiles to provide compounds where m is greater than 1. 
Compounds of Formula 1 where A=CH2 and B=CH2O may be prepared as described in Scheme 13. Treatment of intermediate 80 with an appropriate heteroaromatic nucleophile under basic conditions (e.g. pyrazole, and potassium tert-butoxide in THF) affords 224. Treatment of 224 with trimethoxyvinylsilane, palladium acetate, tri-o-tolulyphopsine in NMP gives vinyl intermediates 226. Hydroboration-oxidation of 226 with 9BBN in THF, followed by oxidation with 30% hydrogen peroxide gave hydroxyethyl intermediate 228. Mitsonobu coupling of 228 with methyl 4-hydroxybenxoate with triphenylphosphine and diethylazodicarboxylate in THF, followed by ester saponication affords retinoid analogs 230.
Also provided is method of preparing a compound of Formula VI, where n and t are 1, R1 is CO2H or CO2-alkyl, R2 is xe2x80x94(CR10R11)mxe2x80x94R12 and R3 is H and R12 is heteroaryl. 
comprising: treating a compound of Formula VII 
where G is a leaving group with a nucleophile R12xe2x80x94H; and when R is CO2-alkyl, hydrolysis with a base.
Compounds of the invention disclosed herein are useful for promoting the repair of damaged alveoli and septation of alveoli. Thus, methods of the invention may be employed to treat pulmonary diseases such as emphysema. The methods of treatment using a compound of the invention disclosed herein also may be used to treat cancer and dermatological disorders.
The retinoic acid receptor agonist selectivity of a compound of the invention may be determined by using ligand binding assays known to the skilled artisan (Apfel et al., Proc. Natl. Acad. Sci., (1992), 89, 7129; Teng et al., J. Med. Chem., (1997), 40, 2445; Bryce et al., U.S. Pat. No. 5,807,900 which are herein incorporated by reference). Treatment with RAR agonists, particularly RAR xcex3 agonists may promote repair of alveolar matrix and septation, which are in important in treating emphysema. Preferably, compounds of the invention are xcex3 selective agonists that bind to the xcex3 receptor with affinities between about 25 nm and about 1000 nm and show a five to ten fold selectivity over binding to the RAR xcex1 receptor. It should be noted that RAR agonists that are not xcex3 selective may be effective in treating emphysema. Transactivation, which is the ability of a retinoid to activate gene transcription when gene transcription is initiated by the binding of a ligand to the particular retinoic acid receptor being tested, may be determined by using methods described in the art (Apfel et al., Proc. Natl. Acad. Sci., (1992), 89, 7129; Bernard et al., Biochem. And Biophys. Res. Comm., (1992), 186, 977 which is herein incorporated by reference.
The suitability of the compounds of the invention in treating dermatological disorders caused by light or age and wound healing may be determined by methods described in the art (Mustoe et al., Science 237, 1333 (1987); Sprugel et al., J. Pathol., 129, 601, (1987), which are herein incorporated by reference). Methods described in the art may be used to determine the usefulness of the compounds of the invention to treating dermatological disorders such as acne or psoriasis (Boyd, Am. J. Med., 86, 568, (1989) and references therein; Doran et al., Methods in Enzymology, 190, 34, (1990), which are herein incorporated by reference). Finally, the ability of the compounds of the invention to treat cancer may also be determined by methods described in the art (Sporn et al., Fed. Proc. (1976), 1332; Hong et al., xe2x80x9cRetinoids and Human Cancerxe2x80x9d in The Retinoids: Biology, Chemistry and Medicine, M. B. Sporn, A. B. Roberts and D. S. Goodman (eds.) Raven Press, New York, 1994, 597-630, which are herein incorporated by reference).
When used to treat or prevent emphysema or related diseases, cancer or dermatological disorders, compounds of the invention may be administered or applied singly, in combination with other agents. The compounds of the invention may also be administered or applied singly, in combination with other pharmaceutically active agents including other compounds of the invention. A compound of the invention can be administered or applied per se or as pharmaceutical compositions. The specific pharmaceutical formulation will depend upon the desired mode of administration, and will be apparent to those having skill in the art. Numerous compositions for the topical or systemic administration of retinoid agonists are known in the art. Any of these compositions may be formulated with a compound of the invention.
Pharmaceutical compositions comprising a compound of the invention may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate processing of compounds of the invention into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
For topical administration a compound of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration. Systemic formulations may be made in combination with a further active agent that improves mucociliary clearance of airway mucus or reduces mucous viscosity. These active agents include but are not limited to sodium channel blockers, antibiotics, N-acetyl cysteine, homocysteine and phospholipids.
For injection, a compound of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks"" solution, Ringer""s solution, or physiological saline buffer. The solution may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, compounds of the invention may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, a compound of the invention can be readily formulated by combination with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. For oral solid formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents and binding agents. If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. If desired, solid dosage forms may be sugar-coated or enteric-coated using standard techniques. Methods for formulating retinoid agonists for oral administration have been described in the art (See, e.g., the formulation of Accutane(copyright), Physicians"" Desk Reference 54th Ed., p. 2610, 2000).
For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols (e.g., polyethylene glycol) oils, alcohols, slightly acidic buffers between pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at between about 5.0 mM to about 50.0 mM) etc. Additionally, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines and the like may be added.
For buccal administration, the compositions may take the form of tablets, lozenges, etc. formulated in conventional manner.
A compounds of the invention may also be administered directly to the lung by inhalation for the treatment of emphysema (see e.g., Tong et al., PCT Application, WO 97/39745; Clark et al., PCT Application, WO 99/47196, which are herein incorporated by reference). For administration by inhalation, a compound of the invention may be conveniently delivered to the lung by a number of different devices. For example, a Metered Dose Inhaler (xe2x80x9cMDIxe2x80x9d) which utilizes canisters that contain a suitable low boiling propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas may be used to deliver compounds of the invention directly to the lung. MDI devices are available from a number of suppliers such as 3M Corporation, Aventis, Boehringer Ingleheim, Forest Laboratories, Glaxo-Wellcome, Schering Plough and Vectura.
Alternatively, a Dry Powder Inhaler (DPI) device may be used to administer a compound of the invention to the lung (See, e.g.,. Raleigh et al., Proc. Amer. Assoc. Cancer Research Annual Meeting, (1999), 40, 397, which is herein incorporated by reference). DPI devices typically use a mechanism such as a burst of gas to create a cloud of dry powder inside a container, which may then be inhaled by the patient. DPI devices are also well known in the art and may be purchased from a number of vendors which include, for example, Fisons, Glaxo-Wellcome, Inhale Therapeutic Systems, ML Laboratories, Qdose and Vectura. A popular variation is the multiple dose DPI (xe2x80x9cMDDPIxe2x80x9d) system, which allows for the delivery of more than one therapeutic dose. MDDPI devices are available from companies such as AstraZeneca, GlaxoWellcome, IVAX, Schering Plough, SkyePharma and Vectura. For example, capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch for these systems.
Another type of device that may be used to deliver a compound of the invention to the lung is a liquid spray device supplied, for example, by Aradigm Corporation. Liquid spray systems use extremely small nozzle holes to aerosolize liquid drug formulations that may then be directly inhaled into the lung.
In one preferred embodiment, a nebulizer device is used to deliver a compound of the invention to the lung. Nebulizers create aerosols from liquid drug formulations by using, for example, ultrasonic energy to form fine particles that may be readily inhaled (see e.g., Verschoyle et al., British J. Cancer, (1999), u, Suppl. 2, 96, which is herein incorporated by reference). Examples of nebulizers include devices supplied by Sheffield/Systemic Pulmonary Delivery Ltd. (See, Armer et al., U.S. Pat. No. 5,954,047; van der Linden et al., U.S. Pat. No. 5,950,619; van der Linden et al., U.S. Pat. No. 5,970,974, which are herein incorporated by reference), Aventis and Batelle Pulmonary Therapeutics.
In another preferred embodiment, an electrohydrodynamic (xe2x80x9cEHDxe2x80x9d) aerosol device is used to deliver a compound of the invention to the lung. EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions (see e.g., Noakes et al., U.S. Pat. No. 4,765,539; Coffee, U.S. Pat. No. 4,962,885; Coffee, PCT Application, WO 94/12285; Coffee, PCT Application, WO 94/14543; Coffee, PCT Application, WO 95/26234, Coffee, PCT Application, WO 95/26235, Coffee, PCT Application, WO 95/32807, which are herein incorporated by reference). The electrochemical properties of a compound of the invention formulation may be important parameters to optimize when delivering this compound to the lung with an EHD aerosol device and such optimization is routinely performed by one of skill in the art. EHD aerosol devices may more efficiently deliver drugs to the lung than existing pulmonary delivery technologies. Other methods of intra-pulmonary delivery of a compound of the invention will be known to the skilled artisan and are within the scope of the invention.
Liquid drug formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices will typically include a compound of the invention with a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier is a liquid such as alcohol, water, polyethylene glycol or a perfluorocarbon. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of compounds of the invention. Preferably, this material is liquid such as an alcohol, glycol, polyglycol or a fatty acid. Other methods of formulating liquid drug solutions or suspension suitable for use in aerosol devices are known to those of skill in the art (see, e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611, which are herein incorporated by reference).
A compound of the invention may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described previously, a compound of the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, a compound of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
Alternatively, other pharmaceutical delivery systems may be employed. Liposomes and emulsions are well known examples of delivery vehicles that may be used to deliver a compound of the invention. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. A compound of the invention may also be delivered in a controlled release system. In one embodiment, a pump may be used (Sefton, CRC Crit. Ref. Biomed. Eng., (1987), u, 201; Buchwald et al., Surgery, (1980), u, 507; Saudek et al., N. Engl. J. Med., (1989), 321, 574). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, N.Y. (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem., (1983), 23, 61; see also Levy et al., Science (1985), 228, 190; During et al., Ann. Neurol., (1989), 25, 351; Howard et al., (1989), J. Neurosurg. 71, 105). In yet another embodiment, a controlled-release system can be placed in proximity of the target of a compound of the invention, e.g., the lung, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115 (1984)). Other controlled-release system may be used (see e.g., Langer, Science, (1990), 249, 1527).
When a compound of the invention is acidic, it may be included in any of the above-described formulations as the free acid, a pharmaceutically acceptable salt, a pro-drug, solvate or hydrate. Pharmaceutically acceptable salts substantially retain the activity of the free acid and may be prepared by reaction with bases. Pharmaceutically acceptable salts include any known suitable salts of retinoic acids known in the art for administration to mammals. Pharmaceutical salts tend to be more soluble in aqueous and other protic solvents than the corresponding free acid form. Similarly, a compound of the invention may be included in any of the above-described formulations as a solvate, hydrate or pro-drug. Preferred pro-drugs include hydrolyzable ester derivatives such as aromatic esters, benzyl esters and lower alkyl esters such as ethyl, cyclopentyl etc. Other pro-drugs are known to those of skill in the pharmaceutical arts.
A compound of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended purpose. Of course, it is to be understood that the amount used will depend on the method of administration.
For use to treat or prevent emphysema, cancer or dermatological disorders, compounds of the invention or compositions thereof, are administered or applied in a therapeutically effective amount. Therapeutically effective amounts of compounds of the invention for systemic administration may be found in the detailed disclosure provided herein.
The pharmacokinetic profile of the compounds of the invention is predictable and can be described by using linear pharmacokinetic theory. Importantly, the pharmacokinetics of compounds of the invention in humans may be readily determined by one of skill in the art. The skilled artisan may determine a range of standard pharmacokinetic parameters after single oral dosing with a compound of the invention using procedures described in the art (see e.g., Khoo et al., J. Clin. Pharm, (1982), 22, 395; Colburn et al., J. Clin. Pharm, (1983), 23, 534; Colburn et al., Eur. J. Clin. Pharm., (19), 23, 689). The skilled artisan may also measure values of these pharmacokinetic parameters after multiple dosing, following procedures described in the art, to determine whether induction or accumulation of the compound of the invention occurs under these circumstances (Brazzel et al., Eur. J. Clin. Pharm., (1983), 24, 695; Lucek et al., Clin. Pharmacokinetics, (1985), 10, 38). Those of skill in the art may estimate the appropriate systemic dosage levels of compounds of the invention necessary to treat emphysema, cancer or dermatological disorders in mammals (preferably, humans) using the pharmacokinetic parameters determined by the above procedures in conjunction with animal model dosage data.
Dosage amounts and intervals may be adjusted individually to provide plasma levels of a compound of the invention which are sufficient to maintain therapeutic effect. Usual patient dosages for administration by injection range from 0.1 xcexcg and about 10.0 mg, preferably, between about 1.0 xcexcg and about 1.0 mg, more preferably, between about 100.0 xcexcg and about 300.0 xcexcg. Therapeutically effective serum levels may be achieved by administering a single daily dose or multiple doses each day.
The amount of a compound of the invention administered will, of course, be dependent on, among other factors, the subject being treated, the subject""s weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. For example, the dosage may be delivered in a pharmaceutical composition by a single administration, by multiple applications or controlled release. Dosing may be repeated intermittently, may be provided alone or in combination with other drugs and will continue as long as required for effective treatment of emphysema.
Preferably, a therapeutically effective dose of a compound of the invention described herein will provide therapeutic benefit without causing substantial toxicity. Toxicity of compounds of the invention may be determined using standard pharmaceutical procedures and may be readily ascertained by the skilled artisan. The dose ratio between toxic and therapeutic effect is the therapeutic index. A compound of the invention will preferably exhibit particularly high therapeutic indices in treating emphysema, cancer or dermatological disorders when compared to other retinoid agonists. The dosage of a compound of the inventions described herein will preferably be within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient""s condition (see, e.g., Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch. 1, p. 1). For example, a therapeutically effective dose of a compound of the invention may be administered either orally or directly into the lung.